Courtagen Life Sciences Blog

Diagnosing Hyperparathyroidism with Genetic Testing

Posted by Meghan Wayne, MS, LGC on Feb 14, 2017 11:39:03 AM


Primary hyperparathyroidism is a disorder of the parathyroid glands caused by overproduction of parathyroid hormone (PTH). This overproduction leads to high blood calcium and causes symptoms such as muscle weakness, fatigue, depression, bone and joint pain, nausea, vomiting, constipation, confusion or impaired thinking and memory, kidney stones, frequent urination, and osteoporosis.

The four parathyroid glands are just one part of the endocrine system, which is responsible for secreting hormones throughout the body. The parathyroid glands are located in the neck behind the thyroid and they produce a hormone called PTH which controls the amount of calcium in our blood and bones. Calcium is important for normal functioning of the nervous, muscular, and skeletal systems. If the calcium in our blood goes too low, the parathyroid glands make more PTH, which causes our level of calcium to go up. If the calcium in our blood goes too high, the parathyroid glands make less PTH, which allows our levels of calcium to decrease.

Primary hyperthyroidism indicates that the disorder originates in the parathyroid glands, whereas secondary hyperparathyroidism occurs when a different problem, such as kidney failure, causes the parathyroid glands to be overactive. Most cases of primary hyperparathyroidism occur when a benign tumor forms in one of the four parathyroid glands. Other cases are caused by the enlargement of two or more parathyroid glands. Rarely, it is caused by cancer of a parathyroid gland.

In the United States, about 100,000 people develop primary hyperparathyroidism each year. It is more common in people between age 50 and 60, and is more common in women than in men. However, hyperparathyroidism may be more common in younger adults than previously thought.


Diagnosing and Treating Hyperparathyroidism

A diagnosis of primary hyperparathyroidism can be made when a person has high blood calcium in addition to high parathyroid hormone levels. Other tests may be necessary to assess for associated complications, such as bone mineral density testing, imaging studies, and urine testing.

The most common treatment for individuals who have symptoms of primary hyperparathyroidism is surgery of the overactive gland. However, there are some exceptions to this and some individuals may be candidates for long-term monitoring. A healthcare provider can assist individuals with hyperparathyroidism in coming up with the most appropriate treatment plan.


Genetics of Hyperparathyroidism

Most individuals with hyperparathyroidism do not have a family history of the disorder. However, there are rare inherited syndromes that can cause primary hyperparathyroidism. A diagnosis of one of these syndromes can help patients, families, and physicians, better understand the underlying cause of a person's symptoms. Affected individuals and their family members are then able to follow a more specific treatment and surveillance plan. The benefits and limitations of genetic testing should be discussed with a healthcare provider. Genetic counselors are specially trained healthcare providers who can provide personalized help to patients and families so that they can understand, and make decisions about, their genetic health.

Below is a summary of the six genes that are analyzed in Courtagen’s Hyperparathyroidism Spotlight Panel. For more information about this and other symptom-based panels, visit our Spotlight Panels page.


CDC73-related disorders are a group of disorders include: parathyroid carcinoma, familial isolated hyperparathyroidism (FIHP), and hyperparathyroidism-jaw tumor syndromes (HPT-JT).

The age of onset of these autosomal dominant disorders is typically in late adolescence or early adulthood. The majority of hyperparathyroidism in these individuals is caused by a single parathyroid adenoma, but 10-15% are caused by parathyroid carcinoma. Additional features of this syndrome include ossifying fibromas of the mandible or maxila (benign but locally aggressive), kidney lesions, and benign and malignant uterine tumors. Treatment may involve the surgical removal of the abnormal parathyroid gland.


Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome associated with varying combinations of more than 20 endocrine and non-endocrine tumors. Parathyroid tumors are the main MEN1-associated endocrinopathy, with onset typically between ages 20-25. Other symptoms of MEN1 include pituitary tumors, well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract, carcinoid tumors, adrenocortical tumors, facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas. Treatment typically includes the surgical removal of the parathyroid.


Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder caused by variants in the RET gene. There are three subtypes: MEN2A, FMTC (familial medullary thyroid carcinoma), and MEN2B. This syndrome is associated with a high risk for the development of medullary carcinoma of the thyroid (MTC). Other features of this syndrome include pheochromocytoma, mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a ‘marfanoid’ habitus. The age of onset depends on the subtype and can range from early childhood to middle age. Treatment may include the surgical removal of the thyroid gland.


Multiple endocrine neoplasia type 4 (MEN4) is an autosomal dominant disorder caused by pathogenic variants in the CDKN1B gene. This syndrome overlaps with symptoms associated with MEN1 and there are no specific clinical features to distinguish MEN4 from MEN1.


Pathogenic variants in the CASR gene can cause familial hypocalciuric hypercalcemia (FHH), which is a benign condition associated with hypercalcemia, low urinary calcium excretion, normal to minimally elevated PTH levels, and frequent hypermagnesemia. The biochemical findings in FHH can overlap with those of primary hyperparathyroidism. The treatment for FHH may not include parathyroidectomy and so this is an important clinical distinction to make. Pathogenic variants in CASR have also been reported in individuals with familial isolated hyperparathyroidism and neonatal severe primary hyperparathyroidism.


Autoimmune polyendocrinopathy syndrome type I is an autosomal recessive disorder caused by pathogenic variants in the AIRE gene. This syndrome is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. Individuals with this condition may have symptoms in multiple part of the body including the skin, eyes, and endocrine system.

References and Further Reading

Topics: Genetics, endocrinology